Multipotent stem cells are known to play a role in healing and repair in response to trauma, disease or disorder. Stem cell mediated repair and healing are achieved by proliferation and differentiation of the stem cells into specialized cell types. For example, mesenchymal stem cells can differentiate into cell types such as bone, cartilage, fat, ligament, muscle, and tendon. In the case of defects in bone, mesenchymal stem cells from the bone marrow, periosteum, and surrounding soft tissue proliferate and differentiate into specialized bone cells. Stem cells can be obtained from embryonic or adult tissues of humans or other animals. As a result of the healing activity of stem cells, much focus has been placed on using stem cells as a treatment to aid in the remodeling of damaged tissue into healthy tissue.
In addition to stem cells, certain growth factors have shown clinical benefit in treatment of bone defects, injuries, disorders, or diseases. Growth and differentiation factors (GDFs) are members of the family of growth factors belonging to the family of bone morphogenetic proteins (BMPs). GDF-5, GDF-6, and GDF-7 (also known as BMP-14, BMP-13, and BMP-12, respectively) are involved in fibrous connective tissue development and healing, as GDFs stimulate production of fibrous connective tissue in vitro and in vivo. However, use of exogenous GDF to aid in tissue repair has been associated with ectopic differentiation of joints, tendon, cartilage, and bone.
Platelet derived growth factor-BB (PDGF-BB) is known to be involved in wound healing (Pierce et al., 1992, Am. J. Pathol., 140:1375-88) and a product containing PDGF-BB has been approved by the FDA for wound healing indications. The data support the safety and benefits of PDGF-BB in healing diabetic ulcers (Smiell et al., 1999, Wound Rep. Reg., 7:335-46). However, PDGF-BB therapy requires repeated applications to achieve clinical efficacy, and PDGF is a potent initiator of fibroblast proliferation which has been linked to tumor growth (Alvarez et al., 2006, Mayo Clin. Proc., 81:1241-57).
In addition to stem cells, fibroblast cells have a role in soft tissue repair. Hernia repair is one of the most common surgical procedures world-wide, with over 20 million repairs performed each year (Kingsnorth, A. and K. LeBlanc, Lancet, 2003, 362:1561-71). In the US there are approximately 100,000 incisional hernia repairs performed annually costing an estimated 1.7 billion dollars (Finan et al., Hernia, 2009, 13:173-82). Despite advances, recurrence rates remain high and range from 3-60% with an average rate of 25% for an initial repair and 44% after a second repair (Afifi, R. Y., Hernia, 2005, 9:310-5; Gray et al., Am J Surg, 2008, 196:201-6). Biocompatible materials have triggered a rapid evolution of hernia repair techniques over the past 10 years. High-tension fascial suturing to strengthen the abdominal wall has been replaced by low-tension repair using biocompatible synthetic mesh (Luijendijk et al., N Engl J Med, 2000, 343:392-98; Flum et al., Ann Surg, 2003, 237:129-35). While a modest improvement over basic suturing, synthetic mesh harbors all the potential pitfalls of implanting a permanent foreign body: adhesions, potential infection, chronic pain, and subsequent mesh removal (Flum et al., Ann Surg, 2003, 237:129-35; Conze et al., Langenbecks Arch Surg, 2007. 392:453-37). Allograft and xenograft materials such as, for example, acellular dermal matrix (ADM) and porcine small intestine submucosa have emerged as favorable alternatives to synthetics, especially in patients with comorbidities, for many types of soft tissue repair including wound, abdominal wall, tendon, breast, dura matter, and rotator cuff repair (Diaz et al., Am Surg, 2006, 72:1181-88; Kim et al., Am J Surg, 2006, 192:705-9; Kish et al., Am Surg, 2005, 71:1047-50; Butler, C. E., Clin Plastic Surg, 2006, 33:199-211; Badylak, S. F., Biomaterials, 2007, 28:3587-93; Longo et al., British Medical Bulletin, 2010, 94:165-88), maintaining an intact elastin lattice, as well as channels for capillary microvascularization. These collagen-based materials promote key components of wound healing and are bioabsorbable. However, complication rates of 24% with recurrence being the most common complication have been reported with these materials, and design improvements are needed (Gupta, A., et al., Hernia, 2006, 10:419-25; Misra, S., et al., Hernia, 2008, 12:247-50). Wound breaking strength represents the amount of force a surgical wound can withstand before failing, and failure occurs when there is a deficient quantity and quality of tissue repair (Franz, M. G., Surg Clin North Am, 2008, 88:1-15, vii). Previous studies have suggested that wound repair integrity reaches a normal breaking strength in 30 days (Franz et al., J Surg Res, 2001, 97: 109-16; Robson, M. C., Surg Clin North Am, 2003, 83:557-69). Fibroblasts are responsible for collagen synthesis and deposition and recovery of wound breaking strength (Franz, M. G., Surg Clin North Am, 2008, 88:1-15, vii). Two days post surgery the inflammatory response subsides and fibroblasts infiltrate the wound, out numbering other cell types by day 4 (Dubay, D. A. and M. G. Franz, Surg Clin North Am, 2003, 83:463-81). Wounds are increasingly challenged during the recovery period as patients return to normal activity. Therefore, a medical device that can become populated with fibroblasts and vascularize faster than other bioprosthetics would reduce the recovery time and increase healing rates to improve repair outcomes.
The leading cause of death in the world today is cardiovascular disease (CVD)(Lopez et al., 2006, 367:1747-57), and the vast majority of CVD is related to impairment of blood flow through diseased atherosclerotic arteries. Stenting and bypass surgery are the most common interventions used to treat occluded arteries. Ideally, the patients own internal mammary artery or the saphenous vein are used as the graft material, but often autologous tissue conduits are not avalible (Faries et al., J Vasc Surg, 2000, 31:1119-27; Zhang et al., J Cell Mol Med, 2007, 11:945-57). Alternatively, synthetic conduits such as expanded polytetrafluoroethylene (ePTFE) or polyethylene terephthalate (Dacron) are used. For large caliber arteries (≧8 mm) Dacron grafts have largely been successful. In contrast, ePTFE, which is commonly used for small caliber arteries (≦6 mm), has a high incidence of failure due to intimal hyperplasia and ongoing surface thrombogenicity (Chlupac et al., Physiol Res, 2009, 58 Suppl 2:S119-39; Zilla et al., Biomaterials, 2007, 28:5009-27). The absence of a selectively permeable and thrombo-resistant endothelium is the main reason for the failure of medium to small-caliber prosthetic vascular grafts (Zhang et al., J Cell Mol Med, 2007, 11:945-57). Ingrowth of a vascular graft from neighboring endothelial cells (EC), and colonization of circulating endothelial progenitor cells (EPC) have resulted in endothelialization of vascular grafts in animal models (Zilla et al., Biomaterials, 2007, 28:5009-27; Shi et al., Blood, 1998, p. 362-67). Successful pre-clinical studies have not translated to the clinic in localizing these cell types to grafts to generate a non-thrombotic surface (Walter et al., Circulation, 2002, p. 3017-24; Werner et al., Circ Res. 2003, p. e17-24; Bhattacharya et al., in Blood, 2000, p. 581-5; Kaushal et al., in Nat Med. 2001, p. 1035-40; Griese et al., in Circulation, 2003, p. 2710-5). Furthermore, new tissue engineering technologies are being developed to generate grafts made of both natural and/or synthetic scaffold material that promote endothelialization (Amiel et al., Tissue Eng, 2006, 12:2355-65; L'Heureux et al., Nat Med, 2006, 12:361-65; Tillman et al., Biomaterials, 2009, 30:583-8). Positive preclinical and clinical studies involving the seeding of cells at the luminal surface of prosthetic vascular grafts prior to implantation supports the concept that ECs and EPCs can improve functional outcomes in vivo (Bhattacharya et al., in Blood. 2000. p. 581-5; Deutsch et al., Surgery, 1999, 126:847-55; Meinhart et al., in Ann Thorac Surg. 2001. p. S327-31; Zilla et al., in J Vasc Surg. 1994. p. 540-8; Parikh, S. A. and E. R. Edelman, Adv Drug Deliv Rev, 2000, 42:139-61). However, EC seeding is laborious, expensive, can introduce contaminants, and is not always possible. Alternatively, mobilizing EPCs from bone marrow followed by capture of EPCs on a vascular graft represents an exciting alternative that eliminates most of the complications associated with cell seeding, and is currently being explored in the clinic with bare metal stents (Aoki et al., J Am Coll Cardiol, 2005, 45:1574-9). In animal models, small numbers of circulating EPCs have been shown to passively attach to implanted grafts and decrease neointima formation following vascular injury (Walter et al., in Circulation. 2002. p. 3017-24; Werner et al., in Circ Res. 2003. p. e17-24). A vascular graft that would promote better endothelialization would reduce intimal hyperplasia and thrombosis.
Therefore, while tissue remodeling can theoretically be achieved by application of cells and/or growth factors at the site of damaged tissue, several obstacles stand in the way of this regenerative technology becoming reality. One obstacle is that cells and/or growth factors injected into many tissues are rapidly cleared via the lymphatics or vascular drainage. In addition, the growth factors can have undesirable ectopic effects. Another obstacle is that the most widely used source of stem cells, bone marrow aspirate, often provides an inadequate amount of stem cells. As a result, use of allogeneic stem cells or culturing of stem cells to increase their number prior to use is frequently still required.
Thus, there remains a need for systems to locally bind, deliver, and retain cells and growth factors to a site of tissue in need of healing or repair. The presently disclosed subject matter provides such systems.